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Article

Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan

by
Aldar A. Munkuev
1,
Nadezhda S. Dyrkheeva
2,
Tatyana E. Kornienko
2,
Ekaterina S. Ilina
2,
Dmitry I. Ivankin
1,
Evgeniy V. Suslov
1,
Dina V. Korchagina
1,
Yuriy V. Gatilov
1,
Alexandra L. Zakharenko
2,
Anastasia A. Malakhova
2,3,
Jóhannes Reynisson
4,
Konstantin P. Volcho
1,*,
Nariman F. Salakhutdinov
1,* and
Olga I. Lavrik
2,5
1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
2
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
3
Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
4
School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK
5
Department of Physical and Chemical Biology and Biotechnology, Altai State University, Pr. Lenina 61, 656049 Barnaul, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(11), 3374; https://doi.org/10.3390/molecules27113374
Submission received: 29 April 2022 / Revised: 15 May 2022 / Accepted: 22 May 2022 / Published: 24 May 2022
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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Abstract

Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (−)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a–14b and 15a–b showed activity against TDP1 at a low micromolar range with IC50 ~5–6 μM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.
Keywords: tyrosyl-DNA phosphodiesterase 1; adamantane; monoterpene; TDP1 inhibitors; 1,2,4-triazole; 1,3,4-thiadiazole; synergy tyrosyl-DNA phosphodiesterase 1; adamantane; monoterpene; TDP1 inhibitors; 1,2,4-triazole; 1,3,4-thiadiazole; synergy

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MDPI and ACS Style

Munkuev, A.A.; Dyrkheeva, N.S.; Kornienko, T.E.; Ilina, E.S.; Ivankin, D.I.; Suslov, E.V.; Korchagina, D.V.; Gatilov, Y.V.; Zakharenko, A.L.; Malakhova, A.A.; et al. Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan. Molecules 2022, 27, 3374. https://doi.org/10.3390/molecules27113374

AMA Style

Munkuev AA, Dyrkheeva NS, Kornienko TE, Ilina ES, Ivankin DI, Suslov EV, Korchagina DV, Gatilov YV, Zakharenko AL, Malakhova AA, et al. Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan. Molecules. 2022; 27(11):3374. https://doi.org/10.3390/molecules27113374

Chicago/Turabian Style

Munkuev, Aldar A., Nadezhda S. Dyrkheeva, Tatyana E. Kornienko, Ekaterina S. Ilina, Dmitry I. Ivankin, Evgeniy V. Suslov, Dina V. Korchagina, Yuriy V. Gatilov, Alexandra L. Zakharenko, Anastasia A. Malakhova, and et al. 2022. "Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan" Molecules 27, no. 11: 3374. https://doi.org/10.3390/molecules27113374

APA Style

Munkuev, A. A., Dyrkheeva, N. S., Kornienko, T. E., Ilina, E. S., Ivankin, D. I., Suslov, E. V., Korchagina, D. V., Gatilov, Y. V., Zakharenko, A. L., Malakhova, A. A., Reynisson, J., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2022). Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan. Molecules, 27(11), 3374. https://doi.org/10.3390/molecules27113374

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